Giotrif Side Effects

Adverse Drug Reaction Overview: The safety evaluation of GIOTRIF is based on the data from more than 3,865 patients, including 2,135 NSCLC patients treated with GIOTRIF monotherapy at or above the recommended dose. The types of adverse drug reactions (ADRs) were generally associated with the EGFR inhibitory mode of action of afatinib. The most frequent ADRs were diarrhea and skin related adverse events as well as stomatitis and paronychia. ILD-like adverse reactions were reported in 0.7% in all GIOTRIF treated patients and 1.3% of patients treated with GIOTRIF in the pivotal clinical trial. Overall, dose reduction led to a lower frequency of common adverse reactions. In patients treated with once daily GIOTRIF 40 mg dose reductions due to ADRs occurred in 57% of the patients. Discontinuation due to ADRs diarrhea and rash was 1.3% and 0% respectively. Bullous, blistering and exfoliative skin conditions have been reported including rare case suggestive of Steven-Johnson.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Pivotal Phase III Trial (LUX-Lung 3): In the pivotal LUX-Lung 3 study, a total of 229 patients not previously treated with an EGFR inhibitor (EGFR TKI-naïve patients) were treated with GIOTRIF with a starting dose of 40 mg once daily until disease progression or intolerance. In the control arm, a total of 111 patients received pemetrexed/cisplatin up to 6 cycles. The median duration of treatment were 336 and 105 days in the GIOTRIF and chemotherapy arms, respectively. Adverse event reported in ≥10% of GIOTRIF treated patients are presented in Table 3 as follows. The incidence of diarrhea and rash AEs was higher in the GIOTRIF treated patients than in those treated with pemetrexed/cisplatin.
Overall, serious AEs were reported in 28.8% patients. The most frequent serious AEs (≥1%) were diarrhea (6.6%), vomiting (4.8%), dyspnea (1.7%), fatigue (1.7%), dehydration (1.3%), pneumonia (1.3%), and stomatitis (1.3%). Fatal adverse events related to GIOTRIF included one event each of dyspnea, ARDS (ILD), sepsis and death (not otherwise specified).
Clinical trial of GIOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GIOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GIOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to the chemotherapy-treated patients (0.9%; n=1).
From pooled data of 2,135 NSCLC patients treated with GIOTRIF monotherapy, events of cardiac failure (acute left ventricular failure, cardiac failure, and diastolic dysfunction) assessed as drug related by the investigator have been reported uncommonly (<1%).
Dose reduction due to AEs occurred in 57% of GIOTRIF-treated patients. Overall dose reduction appeared to have led to a lower frequency of common adverse events (e.g. after first dose reduction, frequency for diarrhea regardless of causality decreased from 96% to 52%).
The most common (>1%) AEs leading to dose reduction in patients treated with GIOTRIF included diarrhea (19.7%), rash (19.2%), paronychia (13.1%), stomatitis (10%), decreased appetite (3.1%), vomiting (3.1%), palmar-plantar erythrodysesthesia syndrome (1.7%), ALT increase (1.3%), AST increase (1.3%), glomerular filtration rate (GFR) decreased (1.3%), nausea (1.3%), and pruritus (1.3%).
Discontinuation of GIOTRIF therapy due to AEs occurred in 14% of patients.
Discontinuation of GIOTRIF therapy due to ADRs occurred in 8% patients. The most common (≥0.5%) AEs that led to discontinuation in the pivotal study were diarrhea (1.3%), dyspnea (0.9%), ILD (0.9%), pleural effusion (0.9%), pneumonia (0.9%) and paronychia (0.9%). (See Tables 3 and 4.)


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Adverse Events Considered Drug Related to GIOTRIF by the Investigator in 1 to 10% patients in LUX-Lung 3 (All Grades): Infection and Infestations: Cystitis (4%), rhinitis (2%), cellulitis (1%), herpes zoster (1%), upper respiratory tract infection (1%).
Blood and Lymphatic System Disorders: Anemia (3%), leukopenia (2%).
Gastrointestinal Disorders: Dyspepsia (4%), dry mouth (4%), abdominal pain (3%), constipation (3%), abdominal distension (2%), abdominal pain upper (2%), gastritis (2%), gastroesphageal reflux disease (2%), dysphagia (1%), abdominal discomfort (1%), gingival bleeding (1%), proctalgia (1%), tongue ulceration (1%).
Hepatobiliary Disorders: Hepatic functions abnormal (2%).
Nervous System Disorder: Dysgeusia (7%), headache (5%), dizziness (4%), hypoesthesia (2%).
Musculoskeletal and Connective Tissue Disorders: Muscle spasm (3%), back pain (2%), myalgia (2%), arthralgia (1%), musculoskeletal chest pain (1%).
Skin and Subcutaneous Tissue Disorders: Alopecia (10%), Palmar-Plantar erythrodysesthesia syndrome (7%), nail disorder (5%), hypertrichosis (3%), pain of skin (3%), skin hyperpigmentation (1%).
Renal and Urinary Disorders: Renal impairment/renal failure (4%), proteinuria (1%).
Eye Disorders: Conjunctivitis (8%), dry eye (5%), keratitis (2%), blepharitis (2%), lacrimation increased (2%), cataract (1%), eye discharge (1%), vision blurred (1%).
Investigations: Alanine aminotransferase increased (7%), aspartate aminotransferase increased (5%), blood alkaline phosphatase increased (2%), hemoglobin decreased (1%).
General Disorders and Administration Site Conditions: Pyrexia (5%), asthenia (4%), edema peripheral (3%), edema (2%), xerosis (2%), chest pain (1%).
Psychiatric Disorders: Insomnia (5%).
Metabolism and Nutritions Disorders: Hypokalemia (6%), dehydration (2%).
Respiratory, Thoratic and Mediastinal Disorders: Rhinorrhea (10%), Cough (3%), nasal dryness (3%), dyspnea (2%), oropharyngeal pain (2%), hemoptysis (1%), interstitial lung disease (1%).
Vascular Disorders: Hypertension (2%).
Injury, Poisoning and Procedural Complications: Wound (1%).
Clinically Important, Afatinib-Related AEs <1% Include: Blood and Lymphatic System Disorders: Lymphopenia, neutropenia.
Cardiac Disorders: Mitral valve incompetence.
Gastrointestinal Disorders: Pancreatitis acute.
General Disorders and Administration Site Conditions: Death.
Infections and Infestations: Sepsis.
Investigations: Blood amylase increased, blood creatine phosphokinase increased, neutrophil count decreased.
Metabolism and Nutrition Disorders: Hypocalcaemia, hyponatraemia.
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary embolism.
Skin and Subcutaneous Tissue Disorders: Hyperkeratosis.